Active immunization with bacteriophage AP205 VLPs results in reduced amyloid load and microgliosis in 5xFAD female mice.

Alzheimer's disease (AD) is the leading cause of dementia worldwide and the accumulation of amyloid β (Aβ) oligomers in the brain parenchyma is one of the main characteristics of AD. Pyroglutamate-modified amyloid β (pE(3)Aβ) forms are highly pathogenic components of Aβ plaques and are viable targets for disease-modifying strategies. Active immunization using virus-like particles (VLPs) represents a promising therapeutic approach to combating AD. Using RNA bacteriophage-based VLPs, we developed and tested a vaccine targeting pE(3)Aβ in 5xFAD female mice. This study utilized the bacteriophage AP205 VLP platform to generate candidate compounds for active immunization. AP205 VLPs were modified to display short pE(3)Aβ peptides. At 2 months of age, 5xFAD female mice received four immunizations with either pE(3)Aβ VLPs or AP205 VLPs. Blood titers were assessed biweekly for the first 45 days and then every 2 months using ELISA. Behavioral tests, including open field, spontaneous alternation, Morris water maze, and elevated zero maze (EZM), were performed at 6 and 8 months of age. Immunohistochemical analyses evaluated levels of Aβ42, pE(3)Aβ, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule-1 (Iba-1). pE(3)Aβ VLPs and AP205 VLPs did not alter cognitive or locomotor performance in 5xFAD mice. The working memory of 8-month-old pE(3)Aβ VLP-treated mice was better than it was at 6-months of age. A moderate reduction in Aβ42 pathology and microglial activation was observed in both vaccinated groups. VLP-based vaccine administration showed no behavioral improvements in 5xFAD mice but demonstrated modest effects on Aβ42 load and microgliosis.